Project Summary Children who suffer traumatic brain injuries (TBI) early in life are more likely to suffer from myriad health concerns including neurological and psychiatric ailments, and substance use disorders, including alcohol abuse, as adults. Clinical studies reveal associations between alcohol abuse and TBI onset at a young age, suggesting long- term effects of TBI on developing neural reward pathways. We present both experimental and clinical preliminary data that have uncovered a sexual dimorphism in posttraumatic alcohol abuse. A clinical analysis of TBI patients revealed a striking sex difference in TBI-related alcohol abuse, such that women who suffered a TBI during adolescent development increased drinking behavior relative to women injured at all other ages. Similar increases in drinking behavior were not apparent in males. Moreover, using a mouse model of childhood TBI, our preliminary data indicate that childhood (21 days old) but not adult (60 days old) TBI greatly increases alcohol consumption and conditioned place preference responses, but only in female mice. This leads us to ask whether differences in sex hormone exposure accounts for sex differences in alcohol abuse rates among TBI patients. Indeed, experimental and clinical studies have reported that sex differences in alcohol drinking emerge at puberty, implicating sex steroid hormones as mediators of this phenomenon. The immediate goal of this application is to understand how sex steroid hormones control sex differences in post-traumatic drinking behavior. Our overall goal is to identify which hormones (ovarian vs. testicular steroids) and when during development they act to mediate sex differences in posttraumatic alcohol consumption. Understanding these mechanisms should prove important for refining treatment and rehabilitation to better target the needs of TBI patients of both sexes and open a large avenue of investigation into the mechanisms of steroid control over alcohol reward systems. The hypothesis of this application is that early organizational exposure to androgens and their estrogenic metabolites organizes the male brain and reduces both basal and post-traumatic drinking behavior. We further predict that exposing females to androgenic hormones early in life will reduce their basal and post-traumatic drinking behavior while early hormone deprivation will increase these parameters in males.